Abstract
Capmatinib (INC280), a highly selective and potent inhibitor of the MET receptor tyrosine kinase, has demonstrated clinically meaningful efficacy and a manageable safety profile in patients with advanced non-small-cell lung cancer harboring MET exon 14-skipping mutations. We investigated the absorption, distribution, metabolism, and excretion of capmatinib in six healthy male volunteers after a single peroral dose of 600 mg 14C-labeled capmatinib. The mass balance, blood and plasma radioactivity, and plasma capmatinib concentrations were determined along with metabolite profiles in plasma, urine, and feces. The metabolite structures were elucidated using mass spectrometry and comparing with reference compounds. The parent compound accounted for most of the radioactivity in plasma (42.9% ± 2.9%). The extent of oral absorption was estimated to be 49.6%; the Cmax of capmatinib in plasma was reached at 2 hours (median time to reach Cmax). The apparent mean elimination half-life of capmatinib in plasma was 7.84 hours. Apparent distribution volume of capmatinib during the terminal phase was moderate-to-high (geometric mean 473 l). Metabolic reactions involved lactam formation, hydroxylation, N-dealkylation, formation of a carboxylic acid, hydrogenation, N-oxygenation, glucuronidation, and combinations thereof. M16, the most abundant metabolite in plasma, urine, and feces was formed by lactam formation. Absorbed capmatinib was eliminated mainly by metabolism and subsequent biliary/fecal and renal excretion. Excretion of radioactivity was complete after 7 days. CYP phenotyping demonstrated that CYP3A was the major cytochrome P450 enzyme subfamily involved in hepatic microsomal metabolism, and in vitro studies in hepatic cytosol indicated that M16 formation was mainly catalyzed by aldehyde oxidase. SIGNIFICANCE STATEMENT: The absorption, distribution, metabolism, and excretion of capmatinib revealed that capmatinib had substantial systemic availability after oral administration. It was also extensively metabolized and largely distributed to the peripheral tissue. Mean elimination half-life was 7.84 hours. The most abundant metabolite, M16, was formed by imidazo-triazinone formation catalyzed by cytosolic aldehyde oxidase. Correlation analysis, specific inhibition, and recombinant enzymes phenotyping demonstrated that CYP3A is the major enzyme subfamily involved in the hepatic microsomal metabolism of [14C]capmatinib.
Highlights
The MET proto-oncogene encodes a receptor tyrosine kinase that plays a role in the activation of signaling pathways involved in cell proliferation, migration, and survival (Sierra and Tsao, 2011; Feng et al, 2014; Smyth et al, 2014; Garajová et al, 2015))
The pathway can be activated via MET gene amplification, which occurs in about 1%–4% of newly diagnosed cases with epidermal growth factor receptor–wild-type non–small-cell lung cancer (NSCLC) (Cappuzzo et al, 2009; Kawakami et al, 2014; Schildhaus et al, 2015)
Radioactivity in plasma was detected for up to 48 hours, and unchanged capmatinib was detected in plasma for up to 72 hours postdose
Summary
The MET proto-oncogene encodes a receptor tyrosine kinase that plays a role in the activation of signaling pathways involved in cell proliferation, migration, and survival (Sierra and Tsao, 2011; Feng et al, 2014; Smyth et al, 2014; Garajová et al, 2015)). Can occur through several mechanisms and may lead to upregulated cell proliferation, survival, and metastasis (Feng et al, 2014; Garajova et al, 2015; Schrock et al, 2016; Tong et al, 2016). One such mechanism is through genomic mutations, including point mutations or insertions/ deletions, leading to exon 14 skipping (Kong-Beltran et al, 2006; Feng et al, 2012; Garajová et al, 2015; Schrock et al, 2016; Salgia, 2017)Kong-Beltran et al, 2006; Feng et al, 2012; Garajova et al, 2015; Schrock et al, 2016; Salgia, 2017). The pathway can be activated via MET gene amplification, which occurs in about 1%–4% of newly diagnosed cases with epidermal growth factor receptor–wild-type non–small-cell lung cancer (NSCLC) (Cappuzzo et al, 2009; Kawakami et al, 2014; Schildhaus et al, 2015)
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